The focus of the Alcohol Research Center at the University of Colorado is on the use of genetic methods to elucidate the neuropharmacological mechanisms by which ethanol brings about its actions on the central nervous system. The use of outbred animals genetically selected for behavioral responses to ethanol provides a unique tool to correlate the neurochemical and neurophysiological measures with these responses. There are now available outbred mice lines that are sensitive (short sleep-SS) or resistant (long-sleep LS) to the acute action of ethanol and other lines that accept alcohol (HA) or reject alcohol (LA). We propose to selectively breed mice for high or low addictability to ethanol. The genetic and biochemical tools are used to study the actions of ethanol on neurotransmitter synthesis, function and metabolism in a number of laboratories of the Center. Techniques of brain transplantation to the anterior chamber of the eye of rats, measurement of density and properties of neurotransmitter receptors, kinetics of enzymes associated with neurotransmitter synthesis and degradation as well as behavioral studies are employed extensively. Studies of ethanol membrane interactions is a major component of these studies and is correlated with the neurotransmitter studies. The effect of ethanol on the developing fetus (fetal alcohol syndrome) in both humans and lower animals will be studied in the coming year. In order to study the influence of the metabolism of ethanol on its central actions, several approaches are taken. We study the actions of several compounds which inhibit or cause induction of ethanol and acetaldehyde metabolism. For these studies we 1) use genetically selected animals which have differential responses to inducing agents for aldehyde dehydrogenase; 2) determine the structure of the biologically active metabolites of compounds which inhibit alcohol or aldehyde metabolism by gas-chromatography-mass spectrometric technique.